A winding road – the many adventures of a promising ADC

Success, they say, rarely comes easy. Never truer than in drug discovery, where the timescale to develop a therapeutic to the point where it can be used on patients is outmatched only by the amount of investment needed to get it there.

But those challenges are surmountable – and the promising state of the biotech landscape in the UK shows start-ups continue to be a hugely important route to success. A route that Myricx Bio – a cancer therapy spinout based on research carried out at Imperial and the Francis Crick Institute – is now firmly established on. The company has just raised £90 million of investment to take its novel treatments with potential for a range of different tumour types, including breast, lung, prostate and gastric cancer, into clinical development.

The approach the company takes is to develop N-myristoyltransferase (NMT) inhibitors as antibody-drug conjugate (ADC) payloads. Whilst ADCs have been promising for some time now, excitingly Myricx Bio’s drug has first-in-class status because of that unique NMT inhibitor payload.

However, says Professor Ed Tate – Myricx Bio Co-founder and Chairman of its Scientific Advisory Board – for an oncology drug that has just received one of the largest Series A investments ever raised by a European academic biotech spinout, it came from remarkably unconventional origins.

suggesting complete and durable tumour regression, at well-tolerated doses, in animal models of solid cancers as well as patient-derived organoid models.

So how did they get here?

Good housekeeping

Ed’s work at the interface between organic chemistry, the life sciences and medicine has seen him focus on processes that ultimately modify living systems. As such he found his way to a lesser-known corner of the post-translational protein modification field – NMT and the protein lipidation process it catalyses, myristoylation.

In the 1980s, when myristoylation and NMT were discovered, the field of post-translational modification was still in its infancy. “At the time the idea that proteins were modified in this way was still quite new,” says Ed. “The processes that were already known – phosphorylation, for example – were having a revolutionary impact on our understanding of cell biology. And later, especially important for drug discovery of course, came kinase inhibitors. The same thing was starting to happen in other areas of post translational modifications, and myristoylation was an example of that.”

In amongst the big hitters of phosphorylation and kinases however, myristoylation took something of a back seat in terms of mass attention. “People were interested in it from a basic biology point of view, but it seemed like a housekeeping enzyme at the time,” says Ed. “It was continuously modifying proteins and there was no way of removing the modification once it was added. Generally, especially in the drug discovery field, people focus more on regulated modifications – things that can be turned on and off, and control rapid events such as cell signalling.”

In terms of a human drug target then, the way forward was unclear. But for Ed there were still opportunities to use NMT to improve human health.

“We started working on this as an anti-parasitic target,” he says. “We understood it had potential as an anti-fungal, but we wanted to know if the same enzyme could be targeted in malaria parasites.”

“We made some really good anti-malarial NMT inhibitors that could cure mice of malaria,” adds Ed. “But even though they were fairly selective, there was always a little bit of inhibition of the human enzyme as well.”

And whilst that level of selectivity might have been good enough, Ed and his lab would never find out if the drug worked in humans. The Bill & Melinda Gates foundation, who had been funding the work, decided to pause further development indefinitely because of the unknown risk of even low activity at the human target. And, as that particular potential NMT drug now sits on the shelf as a promising future direction for malaria treatment, it was its very downfall – its activity on human cells – that seeded an idea for Ed.

A route to cancer

Following up work with Pfizer on high throughput screens on molecules discovered at Imperial, Ed and Andy Bell – a medicinal chemist who led antifungal NMT programmes and was a co-inventor of Viagra at Pfizer – discovered several examples which turned out to strongly interact with the human version of NMT.

“We were inventing molecules that were more and more potent on the human enzyme, and of course nobody wanted to work on those for an antimalarial. But coming from a different drug discovery perspective I saw an opportunity to turn that into something new,” Ed says.

Around this time, there was growing interest in the role myristoylation might have in cancer. And where there is a role for a chemical pathway, naturally the thoughts of a good drug hunter always turn to potential vulnerabilities.

“It seemed it might be possible to take an NMT inhibitor forward as an oncology drug,” says Ed, “because there are multiple substrates of that enzyme that are known anticancer targets. So, the thinking was, if you inhibit NMT you will also inhibit all these downstream targets together, and potentially affect cancer cells to a greater extent than normal cells.”

Once again, the most likely obstacle to a promising new cancer drug lay in the issue of unexplored selectivity, this time between cancer and normal tissue. But Ed remained convinced that there was something in the idea and approached Cancer Research UK.

“CRUK recognised that protein lipidation was a very new and different class of cancer target,” says Ed. “And it didn’t matter that it was coming from the lab of chemist, which is a barrier you can face when you’re asking traditional government funders to support very new ideas. And CRUK and their donors don’t focus so much on where a new idea comes from, they care first and foremost about the potential to one day impact patients.”

Ed won a CRUK Programme Foundation Award and with his collaborators delved deeper into NMT as a drug target, but he says: “It took quite a few more years to really establish how you might use these compounds in oncology.”

Part of the reason for that comes back to that winding path drug development can sometimes take. In Ed’s case, new findings around how viruses use NMT where simply too promising to ignore, and for a while it looked as though the first route to the clinic for NMT inhibitors might even have cured the common cold.

Going viral

“It turns out that many viruses when they infect your cells actually need the human host NMT to modify the virus protein. For example, in the case of the common cold virus, the viral capsid protein that encapsulates the genome in a virus can’t form if it’s not myristoylated,” explains Ed.

So conserved in biology is myristoylation, that the dependence on NMT isn’t limited to rhinoviruses and the common cold, NMT inhibition has begun to show potential for smallpox and even HIV.

Ed started to generate some interesting results using NMT inhibitors on viruses – so good that it prompted his lab to start a parallel program, with the aim of enabling a more direct path to the clinic.

At this stage, Ed met cell biologist and biotech big hitter, Roberto Solari. Solari, who went on to become founding CEO of Myricx Bio, had been a Vice President at GlaxoSmithKline and CEO of MRC Technology (now LifeArc) where he helped create many a spinout company – including G-protein receptor success-story Heptares, and the world’s first fragment-based drug discovery company, Astex.

He had just arrived at Imperial – a chance to move away from big pharma to concentrate again on fundamental science and translation. And when, as chair of Imperial tech transfer fund, Ed’s work on NMT inhibitors landed on his desk, the huge crossover with his work on respiratory viruses simply made it too enticing to ignore.

“There’s actually some very cool biology around this that we discovered with Roberto and other collaborators, and we published some nice papers.”, says Ed. “But it was an unexpected outcome, and it made us think, can we form an antiviral company out of this?”

“Roberto knew how to do translation, he knew how to do spin outs, and he knew the investors.”, says Ed. “So, us two and Andy Bell, who brought his formidable track record from Pfizer, formed an investable team to pitch antivirals.”

There was, however, a problem which ultimately stood in the way of an antiviral spinout. To be used safely, it needed to be clear that the patient was suffering from rhinovirus specifically, and they needed intervene within the first 48 hours with an NMT inhibitor to change the course of infection. The common cold causes about 50% of serious cold infections in vulnerable patients, such as those with severe asthma or COPD, but its symptoms can look a lot like other respiratory viruses. And this was in 2018 – pre-pandemic – before the world had become very familiar with lateral flow tests and the idea of confirming within minutes which virus is responsible for a respiratory infection.

“That would be trivial now, right?” Says Ed. “Everyone would understand that you can test and then self-administer the same day with the drug, through a nasal spray or inhaler. If we had tried this a couple of years later we might have spun out an antiviral company instead of an oncology company!”

Starting small (again)

In the meantime, Ed had also started a group at the Crick Institute. With the opportunity to mix and collaborate with cancer biologists, it became clear they should continue to focus their attention on oncology.

After some successful in vivo work in mouse models, and with the original team remaining committed, they were able to convince a new syndicate of investors to raise enough capital to seed the company, and Myricx Pharma was born.

At this point however, the notion of producing an ADC was not exactly at the front of their mind says Ed. “Seed stage companies have limited resources and need to have a laser like focus – and so we were at the outset fully intent on developing a small molecule therapy, as an orally bioavailable pill.”

And while there were promising early results, the old spectre of selectivity reared its head once more.

“NMT is an essential protein. If you inhibit it for too long at too high a dose, you can start to see toxicity,” says Ed. “Finding the balance is quite tricky, as it turns out. We found that we could get very promising results in blood cancers, but not quite enough efficacy from small molecules in solid tumours. We realised through our CRUK-funded research that this is because it is very difficult to keep NMT inhibitors ‘on target’ for the longer periods – often several days – required to fully regress solid tumours.”

Whilst other groups are pursuing small molecule NMT inhibitors in cancer, for Ed and the Myricx team this approach presents too many potential liabilities. Lack of access to solid tumours and potential toxicity issues meant the team needed a way to get their drugs to their target in another way.

“I was running a separate project in my lab at Imperial on antibody drug conjugates (ADCs) and realised shortly after we founded Myricx that delivery through an antibody conjugate could potentially be a great way to go for NMT inhibitors” says Ed.

After some initial experiments confirmed the promise of this idea, Robin Carr – current Myricx CEO – lead a decisive pivot from small molecules to ADCs and the company was reinvented as Myricx Bio.

A perfect combination

ADCs are certainly not new – the first successful human trial was in 1983 – but until very recently they haven’t quite delivered on their promise. This can at least partially be put down to the fact that the payloads delivered by ADCs are often DNA damaging agents or other cellular poisons which cause collateral damage when they are not successfully restricted to the target cancer cells.

“While it sounds like ADC’s are kind of a guided missile approach, and all the drug should end up in the tumour with no toxicity – that turns out not to be the case,” explains Ed. “The payload actually leaks out in various ways, and that systemic exposure can accumulate toxicity for legacy payloads, particularly on repeated dosing.”

However, with more recent technological advances, ADCs have made a massive comeback in oncology, with the HER2-targeted ADC drug, Enhertu rapidly becoming a blockbuster drug and approvals across many different types of solid tumour. Nevertheless, the vast majority of ADCs in the clinic exploit just a couple of payload mechanisms, and because of this the appetite for novel ADC payloads which can help limit toxicity is huge. This meant the Myricx team knew if they could deliver their potent NMT inhibitors through an antibody, it could be the key to something quite special.

“If you put our ultrapotent NMT inhibitors on an ADC, you can bring the dose down 50 times and still get all the efficacy we were seeing in blood cancers.” says Ed. “But the really exciting is that now it works equally well in solid tumours, because you’re delivering the drug to these tumour cells for the extended period required to target them selectively.”

And should a small amount of the payload leak systematically, the expectation is that it will not stick around long enough to do harm. Having pursued NMT as a target from malaria to viruses and now to oncology, Ed is very optimistic that they have finally beaten the challenge of selectivity once and for all.

“This seems to be the perfect combination – the antibody circulates for exactly the right amount of time to deliver the full power of the NMT inhibitor mechanism, so you can get the ideal combination of efficacy with minimal systemic impact.”

Clinic bound

The recent investment will allow Myricx’s ADCs to move into clinical testing. There are several antibody targets in the company’s extensive portfolio which are clinically validated for solid tumours across large patient populations with substantial unmet need.

This will allow the team to test their approach on a range of different cancer types, including drug-resistant breast, lung, colorectal, prostate and gastric. In terms of patient impact, this could be welcome news indeed. But also, from a translational science perspective, Ed is pleased that there is a real, viable long-term proposition here.

“One issue with a small molecule drug is you’ve only got a limited range of products you can make from a single modality,” he says. “But if we combine it with an ADC, it really becomes a drug discovery platform because you can switch around the antibody part with relative ease. So, I think this is also a much more exciting business proposition.”

So, this NMT-inhibiting ADC that was meant to be a small molecule – which started life as an anti-fungal, then an anti-malarial, then an an-viral before becoming a very promising anti-cancer drug – certainly shows how convoluted the path to drug discovery success can be. Ultimately, of course, the winding road is one worth travelling because it now has great potential to end in real patient benefit.

“I think it can sometimes be difficult for oncologists to appreciate why NMT is such an interesting target, because it is not a conventional cancer driver – it is not mutated in cancer, and so it doesn’t speak to their fundamental interest in genetics. It is really the substrates of NMT which drive cancer and lead to the unique mechanism of action, and this requires quite deep understanding of the target and how it works. So, this has been an interesting and at times quite challenging journey.” says Ed.

“But what I am really pleased about is the fact that CRUK had the vision to see the unique opportunity presented by studying this area. They were among the first funders to support my lab’s research, and their continuous support has been very important for us right from the start all the way through to this important milestone with Myricx, and beyond.”